Higher glycemic variability within the first day of ICU admission is associated with increased 30-day mortality in ICU patients with sepsis

This retrospective cohort study was conducted at one 24-bed medical ICU of a tertiary-care referral hospital with 1514 beds in central Taiwan. Databases of the sepsis management registry and electronic medical records which were collected prospectively were used for analysis. We retrospectively screened all of the adult patients listed in the sepsis management registry database between 1 January 2014 and 31 December 2015. In total, 517 consecutive patients who were admitted to the ICU with sepsis and received protocolized bundle care were included. The bundle care included antibiotic administration, pathogen identification and culture, lactate measurement, fluid resuscitation and vasopressors to stabilize hemodynamics. A protective ventilator strategy was used for the patients with respiratory failure needing mechanical ventilation by targeting tidal volume at 6 ml/kg and limiting the plateau pressure to less than 30 cm H₂O. Glycemic control aiming at keeping blood sugar levels between 150 and 180 mg/dL was achieved using protocolized continuous insulin infusion. Blood glucose was monitored every 2 h for the first 24 h of ICU admission. Given that arterial catheter insertion is part of standard care for patients with sepsis, we used arterial blood instead of capillary blood for point-of-care testing using a glucose meter. The sepsis management registry and electronic medical records databases were used to obtain critical care-associated data, including demographics, comorbidities, Acute Physiology and Chronic Health Evaluation (APACHE) II score, serum glycated hemoglobin (HbA1c), serial glucose data, and other relevant data.

Diabetes mellitus (DM) in this study was defined as patients with a diagnosis of DM before admission and those with HbA1c ≥ 6.5% at admission even without a history of DM [14]. We used two measures to assess GV: mean amplitude of glycemic excursions (MAGE) and coefficient of variation (CoV). Briefly, MAGE is the mean blood glucose value exceeding the standard deviation (SD) from the 24-h mean blood glucose level [15], and CoV represents the ratio of the SD to the mean glucose level [16]. We used MAGE 65 mg/dL as the cut-off point given that a normal MAGE has been reported to be approximately less than 65 mg/dL [15, 17], and a CoV of 30% based on a previous study exploring dysglycemia in patients with sepsis [18].

Data were presented as frequencies (percentages) for categorical variables and as means ± SDs for continuous variables. The Kolmogorov–Smirnov test was used to test normality. Differences between the two groups were analyzed using the Student’s t test or Mann–Whitney U test, while the Chi-square test with Fisher’s exact test were used for categorical variables. Kaplan–Meier analysis was used to test the association between 30-day mortality and GV using MAGE 65 mg/dL as the cut-off point. Variables were considered as candidates for inclusion in the multivariate model if the associated univariate p value was < 0.20, and variables which have been reported to associate with mortality in critically ill patients were also included [19]. A Cox proportional hazards regression model, adjusted for glycemia-associated variables and 30-day mortality-associated variables, was constructed to identify independent variables that predicted 30-day mortality. GV was determined using EasyGV Version 9.0.R2 software. Statistical significance was set at a two-sided p value of < 0.05. All data were analyzed using SPSS software version 22.0 (SPSS Inc., Chicago, IL, USA).

A total of 517 consecutive patients were admitted to the medical ICU due to sepsis between January 2014 and December 2015, of whom 65 were excluded due to a lack of HbA1c data within the past 3 months (Fig. 1). Patients who died within a few hours after ICU admission were hence excluded given that HbA1C was generally checked on day 2 in the study ICU. The remaining 452 patients were eligible for analysis and were divided into high GV (n = 196, 43.4%) and low GV (n = 256, 56.6%) groups using MAGE 65 mg/dL as the cut-off point.

Table 1 summarizes the demographic, GV, and sepsis-related data (Table 1). The mean age was 71.4 ± 14.7 years, and 76.7% of the patients were male. The mean MAGE and CoV were 67 ± 51.1 mg/dL and 23.5 ± 11.2%, respectively. The most common underlying comorbidities were congestive heart failure (31.6%), chronic airway disease (28.1%) and malignancy (23.9%). As expected, those with high GV had a higher HbA1c (6.7 ± 1.8% vs. 5.9 ± 0.9%, p < 0.01) and were more likely to have DM (50.0% vs. 23.4%, p < 0.01) compared with those in the low GV group. The other variables appeared to be comparable between these two groups, except that those with high GV were less likely to be male (71.4% vs. 80.8%, p = 0.03) compared to those in the low GV group. These data suggested that a high GV was prevalent in the patients with sepsis and that it was associated with DM and levels of HbA1c.

The patients with high GV had a higher mean glucose level (184.2 ± 45.1 vs. 148.7 ± 31.0 mg/dL, p < 0.01) and peak glucose level (298.9 ± 76.9 vs. 194.7 ± 50.3 mg/dL) compared to the patients with low GV. With regards to the sepsis-related data, the severity of sepsis was high as evidenced by a high APACHE II score in both groups (27.5 ± 6.6 in the high GV group vs. 27.3 ± 6.6 in the low GV group, p = 0.70). The patients in the high GV group appeared to have a higher serum lactate level at 0 h (29.1 ± 27.4 vs. 24.5 ± 20.1 mg/dL, p = 0.05) and at 24 h (24.1 ± 23.6 vs. 19.9 ± 15.9, p = 0.10) than those in the low GV group. Moreover, the patients in the high GV group had a higher 30-day mortality rate compared to those in the low GV group (36.7% vs. 26.6%, p = 0.03). Given that DM is highly associated with a high GV, we investigated the specific role of DM in the association between GV and 30-day mortality. We used Kaplan–Meier analysis to test the correlation between GV and 30-day mortality, which showed that higher GV was associated with a higher risk of 30-day mortality (log-rank test, p = 0.018) (Fig. 2). The positive association between GV and 30-day mortality remained strong in the non-DM subgroup (log-rank test, p = 0.035), but was no longer present in the DM subgroup (log-rank test, p = 0.254) (Fig. 3). We also analyzed the GV between DM and non-DM groups in this study, and found that the patients with DM had higher GV including MAGE and CoV compared to those without DM. In this cohort, 30-day mortality was unaffected by DM (Fig. 4). Furthermore, in a multivariate Cox proportional hazard regression model adjusted for demographic, glycemia-associated and 30-day mortality-associated data (Additional file 1: Table S1), including age, sex, HbA1c, severe hypoglycemic episodes, cerebrovascular disease, hemoglobin and creatinine, APACHE II score (adjusted hazard ratio (aHR) 1.045, 95% confidence interval (CI) 1.013–1.078), level of lactate at 0 h (aHR 1.009, 95% CI 1.003–1.014), having a diagnosis of chronic airway disease (aHR 0.483, 95% CI 0.305–0.764), level of mean day 1 glucose (aHR 1.008, 95% CI 1.000–1.016), and high MAGE (aHR 1.607, 95% CI 1.008–2.563) were independently associated with 30-day mortality (Table 2). These findings showed that both mean day 1 glucose level and high MAGE were independently associated with 30-day mortality in patients with sepsis, and highlighted the importance of monitoring GV in critically ill patients.

CoV is traditionally used to assess GV. Therefore, we tested the relationship between CoV and MAGE. Pearson correlation analysis showed a high positive correlation between these two measures for GV (MAGE vs. CoV, r = 0.82, p < 0.001) (Fig. 5). The multivariate Cox proportional hazard regression model, adjusted for the same variables used for MAGE, showed that a high GV (determined by CoV > 30%) was also independently associated with high 30-day mortality (aHR 2.593, 95% CI 1.494–4.499) (Table 3). Taken together, our findings suggested that high GV was common in the patients with sepsis, and that it was independently associated with 30-day mortality.